Antitumoral d-homoestra-1,3,5 (10)-trien-3-yl 2-substituted sulfamates

ABSTRACT

This invention relates to 2-substituted D-homo-estra-1,3,5(10)-trien-3-yl sulfamates of general formula I (I), in which R3 means a C1-C5-alkyl or C1-C5-alkyloxy group as well as their use for the production of a pharmaceutical agent for treating tumor diseases, which can be influenced positively by the inhibition of tubulin polymerization. The compounds according to the invention are distinguished by a D-homosubstitution. They have a special action with respect to tubulin polymerization inhibition and can be used, for example, for treating prostate cancer

This invention relates to 2-substituted D-homoestra-1,3,5(10)-trien-3-ylsulfamates and their use for the production of pharmaceutical agentsthat have an antitumor-active activity.

Microtubuli are organelles that occur in most eukaryotic cells and takeover a number of functions there such as mitosis, intracellularmovements, cell migration and the manifestation of the cell shape.Microtubuli are polymers that consist of tubulin, which in turnrepresents a dimer that consists of an α-unit or a β-unit. Theseheterodimers bind two guanosine triphosphate (GTP) molecules, wherebyone of the GTPs is securely bonded and the other is replaceable. In ahead-tail arrangement, the heterodimers polymerize into thread-shapedmacromolecules, the so-called protofilaments, which in turn pile up intotubular organelles, the microtubuli.

Microtubuli are subject to a constant build-up and degradation. Theequilibrium between growth and degradation depends on the availabilityof new GTP-tubulin subunits and the rate of hydrolysis of the secondbonded GTPs. On the plus end, new subunits are cultivated; conversely,on the minus end, subunits diffuse outward.

It is known that cytotoxic substances such as colchicine, vinblastine,vincristine, taxol, epothilone, podophyllotoxin, steganicin,combretastatin and 2-methoxyestradiol influence the build-up ordegradation of mictrotubuli (tubulin polymerization and tubulindepolymerization) and thus are able to influence the cell division in aphase-specific manner. This relates primarily to quick-growing,neoplastic cells, whose growth is largely unaffected by intracellularregulating mechanisms. Active ingredients of this type are in principlesuitable for treating malignant tumors.

Fotsis et al. Nature 1994 368, 237-239 report, moreover, that2-methoxyestradiol inhibits the tumor growth and the angiogenesis.

Cushman et al. J. Med. Chem. 1995 38, 2041-2049 examine the cytotoxicaction as well as the tubulin-polymerization-inhibiting action of2-methoxyestradiol, and report in J. Med. Chem. 1997, 40, 2323-2334,moreover, that 2-alkoxy-6-oximinoestradiol derivatives inhibit thetubulin polymerization as well as the bond of [³H]-colchicine totubulin. The 2-alkoxy-6-oximinoestradiol derivatives that are mentionedhere show comparable activity, relative to the inhibition of tubulinpolymerization, such as 2-ethoxyestradiol, which has a higher activitythan 2-methoxyestradiol.

In contrast, steroid-3-sulfamates are described in the literature asinhibitors of steroid sulfatase:

WO 93/05064 relates to, i.a., compounds of formula

whereby R¹ and R², in each case independently of one another, meanhydrogen or a methyl group, provided that at least one of radicals R¹and R² is an H atom, and the radical-O-polycyclic compound is a3-sterol, whose sulfate ester can be hydrolyzed by an enzyme withsteroid-sulfatase activity. Compounds that are substituted specificallyin the 2-position of the steroid skeleton are not explicitly disclosed.

U.S. Pat. No. 6,011,024 is based on WO 93/05064 and covers, e.g., allcompounds in which the primary sulfamate function is bonded to asix-membered ring. Compounds that are specifically substituted in the2-position of the steroid skeleton are in turn not explicitly disclosed.

WO 96/05216 relates to C2-unsubstituted estra-1,3,5(10)-triene-sulfamatederivatives.

WO 96/05217 relates to pharmaceutical compositions that contain activeingredients of general formula

in which R=NH₂; R³=C₁₋₅-alkoxy group, OH; R⁸, R⁹ and R¹⁰, independentlyof one another, ═H, OH; R⁹ and R¹⁰ together can have the meaning=0. Thepharmaceutical compositions that are disclosed therein can be used forfemale birth control; menopausal HRT and for treatment of gynecologicaland andrological images of disease, such as breast cancer or prostatecancer.

WO 97/14712 relates to steroid sulfamate derivatives of general formula

in which R¹ can represent an acyl, alkoxycarbonyl, aminocarbonyl,sulfonyl or sulfonamidyl group; R² can represent a hydrogen atom or ametal atom; R⁷ and R⁸, independently of one another, can represent H, OHand C₁₋₅-alkoxy; R¹³, R¹² and R¹¹, independently of one another, canrepresent H or OH.

WO 98/42729 relates to 16-halogen-substituted1,3,5-estratriene-3-monosulfamates as well as 3,17β-bissulfamates, whichcan be alkoxy-substituted at C2. The 16-halogen substitution increasesboth the sulfatase-inhibiting action and the estrogeneity of thecorresponding sulfamate derivatives.

The introduction of a 17-sulfamate function in addition to the3-sulfamate function drastically reduces the estrogeneity.

WO 98/24802 relates to sulfamates that inhibit the estrone sulfatase.2-Methoxyestrone sulfamate is explicitly mentioned. As a potentialtherapeutic application, breast cancer, but not prostate cancer, ismentioned in the description.

Also, WO 99/33858 describes estrone sulfatase inhibitors of formula

in which R¹ and R², independently of one another, represent H, alkyl, ortogether piperidine, morpholine, piperazine; R³=H, CN, NO₂, CO₂R⁴; R⁸=H,NO₂, NR⁶R⁷. In the description, breast cancer is mentioned as a possibletherapeutic application.

In WO 99/33859 as well as in US^(o)2002/0032180, anti-estrogeniccompounds are described that are suitable for treatment of different,primarily estrogen-dependent diseases. Preferred compounds have anestra-1,3,5(10)-triene building block and are substituted in 11-positionand 17-position. Especially preferred are17-deoxy-estra-1,3,5(10)-trienes. 2-SubstitutedD-homo-estra-1,3,5(10)-trien-3-yl sulfamates also fall under the generalformulas, but corresponding compounds are not explicitly mentioned.

WO 99/64013 relates to a pharmaceutical composition of a sulfamatederivative with a cell signal modifier (such as, e.g., TNFα).2-Methoxyestrone sulfamate is explicitly claimed as a preferredsulfamate in this combination; but numerous other steroid-3-sulfamatesfall under the scope of the general formula. As a mechanism of actionfor the pharmaceutical compositions according to the invention or forthe steroid-3-sulfamates contained therein (preferably with at least one2-alkoxy substituent), 1) inhibition of the glucose absorption in tumorcells, 2) inhibition of tumor angiogenesies, 3) degradation ofmicrotubuli; 4) inducing of apoptosis are described. WO 00/76487 relatesto substances that inhibit the TNFα-induced aromatase activity. As such,2-alkoxyestrone-3-sulfamates, preferably 2-methoxyestrone sulfamate, areclaimed.

WO 01/18028 describes non-estrogenic estrone sulfatase-inhibitingN-acyl-18a-substituted steroid-3-sulfamates, such as, e.g.,16α-fluoro-2-methoxy-18a-homoestradiol-(N-acetylsulfamate) or16α-fluoro-2-methoxy-18a-homoestrone-(N-acetylsulfamate).

In Cancer 2000, 85, 983-994, the 2-methoxyestradiol, docetaxel andpaclitaxel-induced apoptosis in hepatoma cells and their correlationwith reactive oxygen species are compared.

Potter et al. Int. J. Cancer 2000, 85, 584-589 examine the action of2-methoxyestrone sulfamate in comparison to 2-methoxyestrone on thegrowth of breast cancer cells and induced breast tumors and find that2-methoxyestrone sulfamate has a significant therapeutic potential fortreating breast cancer.

Potter et al. Molecular and Cellular Endocrinology 2000, 160, 61-66examine the inhibition of deoxyglucose absorption in MCF-7 breast cancercells by 2-methoxyestrone and 2-methoxyestrone-3-sulfamate, whichinhibit glucose absorption by 25 to 49% with 10 μm (also2-methoxyestradiol and 2-methoxyestrone), and it follows that thecompounds could have therapeutic potential for inhibiting breast cancerby their capacity to inhibit glucose absorption.

Potter et al. Cancer Research 2000, 60, 5441-5450 describe2-methoxyestrone-sulfamate and 2-ethoxyestrone sulfamate as newantimicrotubulin-active compounds that have in-vitro anti-canceractivity in breast cancer cells and therefore also optionally could beactive in vivo. In J. Steroid Biochem. Mol. Biol. 1999, 69, 227-238, itis reported that the inhibition of the steroid sulfatase activity is animportant starting point in the treatment of hormone-dependent breastcancer. 2-Methoxyestrone sulfamate, 17-deoxyestrone sulfamate andestrone sulfamate are cited explicitly. Monocyclic or bicyclic,non-steroidal sulfamates namely inhibit the steroid sulfatase, but notas effectively as the corresponding steroid derivatives.

The object of this invention consists in making available additionalcompounds that effectively inhibit tubulin polymerization.

The object of this invention is achieved according to the invention bythe provision of 2-substituted D-homoestra-1,3,5(10)-trien-3-ylsulfamates of general formula I:

in which

-   -   R¹ and R², independently of one another, mean a hydrogen atom, a        methyl group, a C₁-C₄-acyl group or a benzoyl group,    -   R³ means a C₁-C₅-alkyl, a C₁-C₅-alkyloxy group or a radical        —O—C_(n)F_(m)H_(o), whereby n=1, 2, 3, 4, 5 or 6, m>1, and        m+o=2n+1,    -   R⁶ and R⁷, independently of one another, mean a hydrogen atom, a        hydroxy group, an amino group or an NHR⁸ group, whereby        -   R⁸ is an acetyl group,    -   or R⁶ and R⁷ together are an oxime NOH,    -   R¹³ is a hydrogen atom or a methyl group,    -   R¹⁹ is a hydrogen atom or a fluorine atom,    -   R²⁰ is a hydrogen atom or a fluorine atom or a hydroxy group or        a C₁-C₅-alkyloxy group or a C₁-C₅-alkyl group or a radical        —C_(n)F_(m)H_(o), whereby n=1, 2, 3, 4, 5 or 6, m>1 and m+o=2n+1        -   or a group SO₂NR¹R²,    -   R¹⁹ and R²⁰ together mean an oxygen atom, a methylene group, a        difluoromethylene group or a monofluoromethylene group or an        oxime        -   NOR²¹, whereby        -   R²¹ is a hydrogen atom or a C₁-C₅-alkyl group,            as well as their pharmaceutically acceptable salts.

In addition, this invention comprises the new compounds aspharmaceutical active ingredients, their production, their therapeuticapplication and the pharmaceutical dispensing forms that contain the newsubstances.

The compounds of general formula (I) according to the invention or theirpharmaceutically acceptable salts can be used for the production of apharmaceutical agent, especially for treating tumor diseases that can beinfluenced positively by the inhibition of tubulin polymerization.

It was determined that the 2-substitutedD-homoestra-1,3,5(10)-trien-3-yl sulfamates according to the inventionmore greatly inhibit in vitro the tubulin polymerization, surprisinglyenough, than 2-methoxyestradiol. The compounds according to theinvention inhibit the proliferation of tumor cells and also show in-vivoantitumor action.

In addition, the compounds according to the invention have better oralbioavailability than 2-methoxyestradiol.

The C₁-C₅-alkyl groups for R³ or R²⁰ can readily be a methyl, ethyl,n-propyl, iso-propyl; n-, iso- or tert-butyl; n-, iso- or neo-pentylgroup.

A formyl, acetyl, propionyl, butyryl, or iso-butyryl radical can standfor an acyl radical R¹ and R².

A methoxy, ethoxy, n-propoxy, iso-propoxy; n-, iso-, or tert-butoxy; n-,iso- or neo-pentoxy group can stand for the C₁-C₅-alkoxy radical R³ orR²⁰.

Preferred according to this invention are compounds of general formulaI, in which:

-   -   R¹ represents H, methyl, acetyl, propionyl, butyryl, in        particular H,    -   R² represents H, acyl,    -   R³ represents methyl, ethyl, methoxy, 2,2,2-trifluoroethoxy,    -   R⁶ and R⁷ both represent hydrogen or together oxime,    -   R¹³ represents H or methyl,    -   R¹⁹ represents H,    -   R²⁰ represents H, OH, C₁-C₅-alkyloxy, in particular H, OH.

The compounds mentioned below as well as their use are especiallypreferred according to the invention:

-   -   1) 2-Methoxy-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-yl        sulfamate (1)    -   2) 2-Methoxy-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-yl        (N-acetyl)-sulfamate    -   3) 2-Methoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate (2)    -   4) 2-Methoxy-17a-homoestra-1,3,5(10)-trien-3-yl        (N-acetyl)-sulfamate    -   5) 2-Methoxy-6-oximino-17a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   6)        2-Methoxy-6-(O-methyloximino)-17a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   7) 6α-Hydroxy-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   8) 6α-Acetylamino-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   9) 2-Methoxy-6-oxo-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate    -   10) 17aα-Hydroxy-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl        sulfamate (3a)    -   11) 17aβ-Hydroxy-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl        sulfamate (3b)    -   12) 2-Methoxy-17a-homoestra-1,3,5(10)-triene-3,17aβ-diyl        bissulfamate (4)    -   13) 2-Methoxy-17a-homoestra-1,3,5(10)-triene-3,17aβ-diyl        bis-(N-acetyl)-sulfamate    -   14) 17a-Difluoro-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   15) 17aα-Fluoro-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   16) 17aβ-Fluoro-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   17) 2-Methoxy-17a-oximino-17a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   18)        2-Methoxy-17a-(methyloximino)-17a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   19) 2,17aβ-Dimethoxy-17a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   20) 2,17aβ-Dimethoxy-17a-homoestra-1,3,5(10)-trien-3-yl        (N-acetyl)-sulfamate    -   21) 17aβ-Ethoxy-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   22) 17aβ-Ethoxy-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl        (N-acetyl)-sulfamate    -   23)        2-Methoxy-17aβ-(n-propoxy)-17a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   24) 2-Methoxy-17aβ-methyl-17a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   25)        17aβ-Difluoromethyl-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   26)        17aβ-Fluoromethyl-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   27) 17aβ-Ethyl-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   28)        2-Methoxy-17a(20)-methylene-17a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   29)        17a(20)-Difluoromethylene-2-methoxy-17a-homoestra-1,3,5(110)-trien-3-yl        sulfamate    -   30)        17a(20)-Fluoromethylene-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   31) 2-Methoxy-17a-oxo-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl        sulfamate    -   32) 2-Methoxy-17a-oxo-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl        (N-acetyl)-sulfamate    -   33) 2-Methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate    -   34) 2-Methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl        (N-acetyl)-sulfamate    -   35) 2-Methoxy-6-oximino-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl        sulfamate    -   36)        2-Methoxy-6-(O-methyloximino)-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl        sulfamate    -   37)        6α-Hydroxy-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl        sulfamate    -   38)        6α-Acetylamino-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl        sulfamate    -   39)        17aβ-Hydroxy-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl        sulfamate    -   40) 2-Methoxy-17a,18a-dihomoestra-1,3,5(10)-triene-3,17aβ-diyl        bissulfamate    -   41) 2-Methoxy-17a,18a-dihomoestra-1,3,5(10)-triene-3,17aβ-diyl        bis-(N-acetyl)-sulfamate    -   42)        17a-Difluoro-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl        sulfamate    -   43)        17aα-Fluoro-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl        sulfamate    -   44)        17aβ-Fluoro-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl        sulfamate    -   45)        2-Methoxy-17a-oximino-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl        sulfamate    -   46)        2-Methoxy-17a-(methyloximino)-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl        sulfamate    -   47) 2,17aβ-Dimethoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl        sulfamate    -   48)        17aβ-Ethoxy-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl        sulfamate    -   49)        2-Methoxy-17aβ-(n-propoxy)-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl        sulfamate    -   50)        2-Methoxy-17aβ-methyl-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl        sulfamate    -   51)        17aβ-Difluoromethyl-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl        sulfamate    -   52)        17aβ-Fluoromethyl-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl        sulfamate    -   53)        17aβ-Ethyl-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl        sulfamate    -   54)        2-Methoxy-17a(20)-methylene-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl        sulfamate    -   55)        17a(20)-Difluoromethylene-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl        sulfamate    -   56)        17a(20)-Fluoromethylene-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl        sulfamate    -   57) 2-Ethyl-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate    -   58) 2-Ethyl-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-yl        (N-acetyl)-sulfamate    -   59) 2-Ethyl-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate    -   60) 2-Ethyl-17a-homoestra-1,3,5(10)-trien-3-yl        (N-acetyl)-sulfamate    -   61) 2-Ethyl-17aβ-hydroxy-17a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   62) 2-Ethyl-17a-homoestra-1,3,5(10)-triene-3,17aβ-diyl        bissulfamate    -   63) 2-Ethyl-17a-homoestra-1,3,5(10)-triene-3,17aβ-diyl        bis-(N-acetyl)-sulfamate    -   64) 2-Ethyl-17aβ-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   65) 2-Ethyl-17aβ-ethoxy-17a-homoestra-1,3,5(10)-trien-3-yl        sulfamate        Pharmacological Data        1. Inhibition of Tubulin Polymerization

The compounds according to the invention were tested in various models.

The compounds of general formula I according to the invention aredistinguished in that they more greatly inhibit tubulin polymerizationthan 2-methoxyestradiol. The in-vitro testing of the tubulinpolymerization influence was performed as follows:

According to Shelanski et al. (Shelanski et al. Proc. Natl. Acad. Sci.USA 1973, 70, 765-8), microtubular protein was purified from pig brainsvia cydic assembling/disassembling. The buffer system used had thefollowing composition: 20 mmol of PIPES(1,4-piperazine-diethane-sulfonic acid, pKa 6.8), 80 mmol of NaCl, 0.5mmol of MgCl₂, 1 mmol of EGTA [ethyleneglycol-bis-(2-aminoethylene)-tetraacetic acid].

For active ingredient testing, protein concentrations of 1 mg/ml (about10⁻⁵ mmol of tubulin) were used. The determination of protein wascarried out according to the Lowry Method (Lowry et al. J. Biol. Chem.1951, 193, 265-75) with bovine serum albumin as a standard. Theassembling of microtubuli was carried out in the presence of 0.25 mmolof GTP and heating the samples to 37° C.

The microtubulus formation was examined by means of turbidimetry at awavelength of 340 nm. The state of equilibrium, in which themicrotubular protein exhibits no increase in the assemblateconcentration (corresponding to the microtubulus concentration) and theturbidity value no longer exhibits an increase, is typically reachedafter 20 minutes.

Testing of the active ingredients was carried out by their addition atthe beginning of the assembling or in the state of equilibrium.Deviations of turbidity curves from the control characterize itsactivity. To monitor action and to evaluate the measured turbidityvalues, a transmission electron microscopic study (CEM 902 A,Zeiss/Oberkochen) of the assemblates was always performed after negativestaining with 1% aqueous uranyl acetate.

TABLE 1 Inhibition of Tubulin Polymerization Compound IC₅₀ [μm]2-Methoxyestradiol 2.7 (2) 0.952. Inhibition of Cell Proliferation

The compounds according to the invention are distinguished by a potentinhibition of cell proliferation.

Cell cultures of the following cell lines were prepared in 96-wellmicrotiter plates:

-   -   1. MaTu/ADR multidrug-resistant human breast tumor cells (Epo        GmbH Berlin), 5000 cells/well.    -   2. HCT116 human colon tumor cells (ATCC CCL-247), 3000        cells/well.    -   3. NCl-H460 human non-small-cell lung cancer cells (ATCC        HTB-177), 3000 cells/well.    -   4. DU145 human prostate tumor cells (ATCC HTB-81), 5000        cells/well.    -   5. HMVEC human primary dermal microvascular endothelial cells,        7500 cells/well.

After 24 hours of incubation in a cell culture incubator at 37° C., thecells of a microtiter plate were stained with crystal violet (referenceplate), while the cells in the test plates were incubated for 4 dayswith the test substances in the concentrations 0.1-10 μm, as well aswith the DMSO solvent by itself (solvent control). The cellproliferation was determined by staining cells with crystal violet. Theextinction of the crystal violet was determined by photometry at 595 nm.The percentage of the change in the cell number in the test plates wasdetermined after the extinction values were normalized to the referenceplate (0%) and to the solvent control (100%). The semi-maximalinhibition of the cell growth (IC50) was determined as the substanceconcentration, in which 50% of the cell number of the solvent controlswere present.

TABLE 2 Inhibition of Cell Proliferation IC50 [μm] MaTu/ CompoundNCl-H460 HCT116 DU145 ADR HMVEC Taxol 0.004 0.004 0.004 0.4 0.0042-Methoxy- 1.8 1.1 1.9 0.2 2.2 estradiol (1) 0.18 0.18 0.5 <0.1 0.22 (2)0.6 0.6 0.6 0.2 0.5 (4) 1.8 1.8 2.8 0.8 0.6Dosage

In general, satisfactory results can be expected when the daily dosescomprise a range of 5 μg to 50 mg of the compound according to theinvention per kg of body weight. In larger mammals, for example inhumans, a recommended daily dose is in the range of 10 μg to 30 mg perkg of body weight.

Suitable dosages for the compounds according to the invention are from0.005 to 50 mg per day per kg of body weight, depending on the age andconstitution of the patient, whereby the necessary daily dose can beadministered one or more times.

Based on the special depot action of the estrogen-sulfamates, thecompounds according to the invention can, however, also be administeredat greater intervals than once per day.

The formulation of the pharmaceutical preparations based on the newcompounds is carried out in a way that is known in the art, by theactive ingredient being processed with the vehicles, fillers, substancesthat influence decomposition, binding agents, moisturizing agents,lubricants, absorbing agents, diluents, flavoring correctives, coloringagents, etc., that are commonly used in galenicals and converted intothe desired form of administration. In this case, reference is made toRemington's Pharmaceutical Science, 15^(th) Edition, Mack PublishingCompany, East Pennsylvania (1980).

For oral administration, in particular tablets, coated tablets,capsules, pills, powders, granulates, lozenges, suspensions, emulsionsor solutions are suitable.

For parenteral administration, injection and infusion preparations arepossible.

For intraarticular injection, correspondingly prepared crystalsuspensions can be used.

For intramuscular injection, aqueous and oily injection solutions orsuspensions and corresponding depot preparations can be used.

For rectal administration, the new compounds can be used in the form ofsuppositories, capsules, solutions (e.g., in the form of enemas) andointments both for systemic and for local therapy.

For pulmonary administration of the new compounds, the latter can beused in the form of aerosols and inhalants.

For topical application, formulations in gels, ointments, fattyointments, creams, pastes, powders, milks and tinctures are possible.The dosage of the compounds of general formula I should be 0.01%-20% inthese preparations to achieve an adequate pharmacological action.

This invention comprises the compounds of general formula I and theiruse for the production of a pharmaceutical agent, in particular fortreating tumor diseases that can be influenced positively by theinhibition of tubulin polymerization.

The compounds of general formula I according to the invention arepreferably used for the production of a pharmaceutical agent, inparticular for treating tumor diseases of the male and female gonads,male and female sex organs including the mammary glands, in particularof prostate cancer or breast cancer.

This invention also relates to pharmaceutical compositions that containat least one especially preferred compound according to the invention,optionally in the form of a pharmaceutically/pharmacologicallycompatible salt, without or together with pharmaceutically compatibleadjuvants and/or vehicles.

These pharmaceutical compositions and pharmaceutical agents can beprovided for oral, rectal, vaginal, subcutaneous, percutaneous,intravenous or intramuscular administration. In addition to commonlyused vehicles and/or diluents, they contain at least one especiallypreferred compound according to the invention.

The pharmaceutical agents of the invention are produced with commonlyused solid or liquid vehicles or diluents and the commonly usedpharmaceutical-technical adjuvants corresponding to the desired type ofadministration at a suitable dosage in a known way. The preferredpreparations consist in a dispensing form that is suitable for oraladministration. Such dispensing forms are, for example, tablets, filmtablets, coated tablets, capsules, pills, powders, solutions orsuspensions or else depot forms.

The pharmaceutical compositions that contain at least one of thecompounds according to the invention are preferably administered orally.

Parenteral preparations such as injection solutions are also considered.In addition, for example, suppositories and agents for vaginalapplication can also be mentioned as preparations.

Corresponding tablets can be obtained by, for example, mixing activeingredient with known adjuvants, for example inert diluents such asdextrose, sugar, sorbitol, mannitol, polyvinyl pyrrolidone, explosivessuch as corn starch or alginic acid, binding agents such as starch orgelatin, lubricants such as magnesium stearate or talc and/or agents forachieving a depot effect such as carboxyl polymethylene, carboxylmethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tabletscan also consist of several layers.

Coated tablets accordingly can be produced by coating cores, which areproduced analogously to the tablets, with agents that are commonly usedin tablet coatings, for example, polyvinyl pyrrolidone or shellac, gumArabic, talc, titanium oxide, or sugar. In this case, the shell of thecoated tablets can also consist of several layers, whereby the adjuvantsthat are mentioned above in the tablets can be used.

Solutions or suspensions with the compounds of general formula Iaccording to the invention can contain additional taste-improving agentssuch as saccharine, cyclamate or sugar, as well as, e.g., flavoringsubstances such as vanilla or orange extract. In addition, they cancontain suspending adjuvants such as sodium carboxy methyl cellulose orpreservatives such as p-hydroxybenzoates.

Capsules that contain the compounds of general formula I can be producedby, for example, the compound(s) of general formula I being mixed withan inert vehicle such as lactose or sorbitol and encapsulated in gelatincapsules.

Suitable suppositories can be produced by, for example, mixing withvehicles that are provided for this purpose, such as neutral fats orpolyethylene glycol or derivatives thereof.

For therapy of prostate cancer, the compounds according to the inventioncan be administered in combination with one or more of the followingactive ingredients:

-   -   1) Antiandrogens such as CPA, flutamide, casodex, etc.    -   2) Gonadotrophic hormone (GnRH) agonists    -   3) 5α-Reductase inhibitors such as finasteride    -   4) Cytostatic agents    -   5) VEGF-kinase inhibitors    -   6) Antigestagens    -   7) Antiestrogens    -   8) Antisense oligonucleotides    -   9) EGF antibodies    -   10) Estrogens

Moreover, the compounds of general formula I according to the inventioncan be used for therapy and prophylaxis of other pathologic conditionsthat are not mentioned above.

The compounds of general formula I according to the invention can beproduced as described below:

The functionalization of C-atom 2 of an estra-1,3,5(10)-trien-17-onederivative is preferably carried out by Friedel-Crafts acylation asdescribed in the literature (T. Nambara et al. Chem. Pharm. Bull. 1979,18, 474-480).

After changing the protective group in 3-position, a2-carboxy-estra-1,3,5(10)-trien-17-one is generated by Baeyer-Villigeroxidation (M. B. Smith, J. March, March's Advanced Organic Chemistry,5^(th) Edition, Wiley Sons 2001, 1417-1418 and literature cited there).The ester is saponified and converted with the corresponding alkylhalide under basic conditions into a 2-alkyl ether. Alternately, the17-ketone as known can now be reduced and etherified. The cleavage ofthe protective group in 3-position is carried out as described in theliterature (T. W. Greene, P. G. M. Wuts, Protective Groups in OrganicSynthesis, Wiley & Sons, 1999, 249-275). This process or other processesknown from the literature (P. N. Rao, J. W. Cessac, Steroids 2002, 67,1065-1070 and literature cited there) can be used according to the17a-homo or 17a,18a-dihomo derivatives.

The 2-acyl derivatives that are preferably obtained by Friedel-Craftsacylation can be converted by reduction with sodium borohydride andsubsequent hydrogenation into the corresponding 2-alkyl derivatives.

The corresponding 17a-oxime, 17a-alkylene (so-called Wittig reaction,see, e.g., S. Schwarz et al. Pharmazie 2001, 56, 843-849),17a-difluoromethylene (Wadsworth-Emmons Reaction, S. R. Piettre, L.Cabanas, Tetrahedron Lett. 1996, 37, 5881-4884), and 17α,β-alkylderivatives can also be produced from the 2-functionalized derivatives(e.g., R. H. Peters et al., J. Med. Chem. 1989, 32, 1642; G. E. Agostonet al. WO 02/42319) and then are sulfamoylated in 3-position.

According to Cushman et al (J. Med. Chem. 1997, 40, 2323), the synthesisof 6-functionalized estrogen derivatives is carried out by oxidation ofthe acetyl-protected estrogen derivative with chromium trioxide.

Starting from the 2-functionalized 17-keto derivatives, 17-oxiranes (M.Hübner, I. Noack, J. prakt. Chem. 1972, 314, 667) and from them thecorresponding 17a-homo derivatives (M. Hübner, K. Ponsold, Z. Chem.1982, 22, 186) can be produced.

17a-Fluorinated derivatives can be produced from the corresponding17a-oxo or 17a-hydroxy derivatives with diethylamino-sulfur trifluoride(M. Hudlicky, Org. Reactions 1988, 35, 513; J. T. Welch, Fluorine inBioorganic Chemistry 1991, John Wiley, New York; S. Rozen et al.Tetrahedron Lett. 1979, 20, 1823-1826) and then sulfamoylated.

This invention is explained in more detail based on the examples below,without being limited thereto:

PRODUCTION PROCESS General Instructions 1 for the Production of17a-Homoestra-1,3,5(10)-trien-3-yl Sulfamates

One equivalent of a 17a-homoestra-1,3,5(10)-triene derivative inmethylene chloride is dissolved or suspended while being stirred andmixed with 5 equivalents of 2,6-di-tert-butylpyridine. Then, 10equivalents of sulfamoyl chloride are added under argon and stirred atroom temperature. The solution is stirred until conversion is completed(TLC monitoring, 1-5 hours) and then mixed with water. In acid-sensitivecompounds, buffering is done in advance with about 10 equivalents oftriethylamine. The aqueous phase is extracted several times withdichloromethane or ethyl acetate. The combined organic phases are driedon sodium sulfate and concentrated by evaporation in a vacuum and thenpurified by flash chromatography.

General Synthesis Instructions 2 for Acylation of Sulfamates

One equivalent of the 17a-homoestra-1,3,5(10)-triene-sulfamate orbissulfamate is dissolved in pyridine and mixed with 5 equivalents ofanhydride while being cooled with ice (0 to 5° C.). Stirring iscontinued for 1 hour at room temperature and then mixed with water. Theaqueous phase is extracted several times with dichloromethane or ethylacetate. The combined organic phases are washed with 6N hydrochloricacid and then with water and sodium chloride solution. Then, it is driedon sodium sulfate and concentrated by evaporation in a vacuum and thenpurified by flash chromatography.

The following compounds according to the invention were producedaccording to the above-mentioned instructions:

EXAMPLE 1 2-Methoxy-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-yl Sulfamate(1)

3.61 g of17α-azidomethyl-3,17β-dihydroxy-2-methoxy-estra-1,3,5(10)-triene and 7.5g of sodium iodide were suspended in 250 ml of acetonitrile and mixedslowly at room temperature with 15 ml of trimethylsilyl chloride. After4 hours, another 4 ml of trimethylsilyl chloride was added, and afteranother 2.5 hours, it was mixed with saturated sodium thiosulfatesolution and water and extracted with dichloromethane (3×). The combinedorganic phases were washed with aqueous sodium bicarbonate solution,dried and concentrated by evaporation in a rotary evaporator. Flashchromatography (cyclohexane/ethyl acetate=10:1→7:1→5:1) yielded 2.12 g(67%) of 3-hydroxy-2-methoxy-17a-oxo-17a-homoestra-1,3,5(10)-triene ascolorless crystals.

¹H-NMR (CDCl₃): δ=1.13 (s, 3H: 18-CH₃), 2.62-2.71 (m, 1H: 17-H), 2.77(dd, 2H: 6-CH₂), 3.86 (s, 3H; 2-OCH₃), 5.48 (s, 1H; 3-OH), 6.63, 6.78 (2s, 2H; 1-H, 4-H).

492 mg of 3-hydroxy-2-methoxy-17a-oxo-17a-homoestra-1,3,5(10)-trienewere reacted to form the product according to the general synthesisinstructions and then purified by flash chromatography(cyclohexane/ethyl acetate=3:1→2:1). 545 mg (89%) of2-methoxy-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate (1) wasobtained as colorless crystals.

¹H-NMR (CDCl₃): δ=1.13 (s, 3H; 18-CH₃), 2.63-2.71 (m, 1H; 17-H),2.74-2.84 (m, 2H; 6-CH₂), 3.88 (s, 3H; 2-OCH₃), 5.00 (s, 2H; NH₂), 6.93,7.04 (2 s, 2H; 1-H, 4-H).

EXAMPLE 2 2-Methoxy-17a-homoestra-1,3,5(10)-trien-3-yl Sulfamate (2)

600 mg of 3-hydroxy-2-methoxy-17a-oxo-17a-homoestra-1,3,5(10)-triene wasdissolved in 20 ml of triethylene glycol and mixed under argon with 15ml of hydrazine-monohydrate and 0.8 g of potassium hydroxide. Then, itwas heated for 2 hours to 130° C. and then for another 1.5 hours to 200°C. After cooling to room temperature, it was acidified with 6Nhydrochloric acid and extracted with dichloromethane (3×). The combinedorganic phases were washed with saturated sodium bicarbonate solution,dried and concentrated by evaporation in a rotary evaporator. Flashchromatography (cyclohexane/ethyl acetate=100:1→50:1→20:1) yielded 541mg (94%) of 3-hydroxy-2-methoxy-17a-homoestra-1,3,5(10)-triene ascolorless crystals.

¹H-NMR (CDCl₃): δ=0.85 (s, 3H; 18-CH₃), 2.71-2.74 (m, 2H; 6-CH₂), 3.85(s, 3H; 2-OCH₃); 5.41 (s, 1H: 3-OH), 6.62, 6.79 (2 s, 2H; 1-H, 4-H).

253 mg of 3-hydroxy-2-methoxy-17a-homoestra-1,3,5(10)triene was reactedto form the product according to general synthesis instructions 1 andthen purified by flash chromatography (toluene/ethyl acetate=20:1→10:1).217 mg (68%) of 2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate(2) was obtained in the form of colorless crystals.

¹H-NMR (CDCl₃): δ=0.85 (s, 3H; 18-CH₃), 2.67-2.82 9m, 2H: 6-CH₂), 3.86(s, 3H: 2-OCH₃), 4.97 (s, 2H: NH₂), 6.93, 7.02 (2 s, 2H; 1-H, 4-H).

EXAMPLE 3 17aα-Hydroxy-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-ylSulfamate (3a) and17aβ-Hydroxy-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl Sulfamate (3b)

298 mg of 2-methoxy-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate(2) was dissolved in 20 ml of methanol and 10 ml of tetrahydrofuran andmixed with 115 mg of sodium borohydride while being cooled with ice.After 2 hours, it was mixed with acetone and concentrated by evaporationin a rotary evaporator. The residue was acidified with 6N hydrochloricacid and extracted with dichloromethane (2×). The combined organicphases were washed with saturated sodium bicarbonate solution, dried andconcentrated by evaporation in a rotary evaporator. Flash chromatography(n-hexane/ethyl acetate=3.2→1:1) yielded 35 mg (12%) of the α-epimer 3aas well as 276 mg (92%) of the β-epimer 3b as amorphous solids.

3a: ¹H-NMR (CDCl₃): δ=0.86 (s, 3H; 18-CH₃), 3.42 (dd,³J_(eq)=³J_(ax)=2.7 Hz, 1H; 17aβ-H), 3.86 (s, 3H; 2-OCH₃), 5.14 (s, 2H;NH₂), 6.92, 7.02 (2 s, 2H; 1-H, 4-H).

3b: ¹H-NMR (CDCl₃): δ=0.84 (s, 3H; 18-CH₃), 3.25 (dd, ³J=4.3 and 11.3Hz, 1H; 17aα-H), 3.87 (s, 3H; 2-OCH₃), 5.07 (s, 2H; NH₂), 5.29 (s, 1H;OH), 6.93, 7.03 (2 s, 2H; 1-H, 4-H).

EXAMPLE 4 2-Methoxy-17a-homoestra-1,3,5(10)-triene-3,17aβ-diylBissulfamate (4)

62 mg of 17aβ-hydroxy-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-ylsulfamate (3b) was reacted to form the product according to generalsynthesis instructions and then purified by flash chromatography(toluene/ethyl acetate=3:1). 55 mg (74%) of2-methoxy-17a-homoestra-1,3,5(10)-triene-3,17aβ-diyl bissulfamate (4)was obtained as colorless oil, which slowly crystallized.

¹H-NMR (DMSO-d₆): δ=0.84 (s, 3H; 18-CH₃), 3.76 (s, 3H; 2-OCH₃), 4.06(dd, ³J=4.3 and 11.7 Hz, 1H; 17aα-H), 6.97, 7.00 (2 s, 2H; 1-H, 4-H),7.37 (s, 2H; NH₂), 7.82 (s, 2H; NH₂).

1. A 2-Substituted D-homoestra-1,3,5(10)-trien-3-yl sulfamate of formulaI

in which R¹ and R² are, independently of one another, a hydrogen atom, amethyl group, a C₁-C₄-acyl group or a benzoyl group, R³ means aC₁-C₅-alkyl, a C₁-C₅-alkyloxy group or a radical —O—C_(n)F_(m)H_(o),wherein n=1, 2, 3, 4, 5 or 6, m>1, and m+o=2n+1, R⁶ and R⁷, areindependently of one another, a hydrogen atom, a hydroxy group, an aminogroup or an NHR⁸ group, wherein R⁸ is an acetyl group, or R⁶ and R⁷together are an oxime NOH, R¹³ is a hydrogen atom or a methyl group, R¹⁹is a hydrogen atom or a fluorine atom, R²⁰ is a hydrogen atom or afluorine atom or a hydroxy group or a C₁-C₅-alkyloxy group orC₁-C₅-alkyl group or a radical —C_(n)F_(m)H_(o), wherein n=1, 2, 3, 4, 5or 6, m>1 and m+o=2n+1, or a group SO₂NR¹R², or R¹⁹ and R²⁰ togethermean an oxygen atom, a methylene group, a difluoromethylene group or amonofluoromethylene group or an oxime NOR²¹, wherein R²¹ is a hydrogenatom or a C₁-C₅-alkyl group, or a pharmaceutically acceptable saltthereof.
 2. A 2-Substituted D-homoestra-1,3,5(10)-trien-3-yl sulfamateaccording to claim 1, wherein R³ represents a methyl, ethyl, methoxy,ethoxy or 2,2,2-trifluoroethoxy group.
 3. A 2-SubstitutedD-homoestra-1,3,5(10)-trien-3-yl sulfamate according to claim 2, whereinR³ represents a methoxy group.
 4. A 2-SubstitutedD-homoestra-1,3,5(10)-trien-3-yl sulfamate according to claim 1, whereinR⁶ and R⁷ in each case represent a hydrogen atom.
 5. A 2-SubstitutedD-homoestra-1,3,5(10)-trien-3-yl sulfamate according to claim 1, whereinR¹⁹ represents a hydrogen atom.
 6. A 2-SubstitutedD-homoestra-1,3,5(10)-trien-3-yl sulfamate according to claim 1, whereinR²⁰ represents a hydrogen atom or a hydroxy group.
 7. A 2-SubstitutedD-homoestra-1,3,5(10)-trien-3-yl sulfamate according to claim 1, whereinR¹ represents a hydrogen atom.
 8. A 2-SubstitutedD-homoestra-1,3,5(10)-trien-3-yl sulfamate according to claim 1, whereinR² represents a hydrogen atom or an acyl group.
 9. A 2-SubstitutedD-homoestra-1,3,5(10)-trien-3-yl sulfamate according to claim 1, whereinR¹³ represents a hydrogen atom or a methyl group.
 10. A 2-SubstitutedD-homoestra-1,3,5(10)-trien-3-yl sulfamate according to claim 1, whichis 1) 2-Methoxy-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate 2)2-Methoxy-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-yl(N-acetyl)-sulfamate 3) 2-Methoxy-17a-homoestra-1,3,5(10)-trien-3-ylsulfamate 4) 2-Methoxy-17a-homoestra-1,3,5(10)-trien-3-yl(N-acetyl)-sulfamate 5)2-Methoxy-6-oximino-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate 6)2-Methoxy-6-(O-methyloximino)-17a-homoestra-1,3,5(10)-trien-3-ylsulfamate 7) 6α-Hydroxy-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-ylsulfamate 8) 6α-Acetylamino-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-ylsulfamate 9) 2-Methoxy-6-oxo-17a-homoestra-1,3,5(10)-trien-3-ylsulfamate 10) 17aα-Hydroxy-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-ylsulfamate 11) 17aβ-Hydroxy-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-ylsulfamate 12) 2-Methoxy-17a-homoestra-1,3,5(10)-triene-3,17aβ-diylbissulfamate 13) 2-Methoxy-17a-homoestra-1,3,5(10)-triene-3,17aβ-diylbis-(N-acetyl)-sulfamate 14)17a-Difluoro-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate 15)17aα-Fluoro-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate 16)17aβ-Fluoro-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate 17)2-Methoxy-17a-oximino-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate 18)2-Methoxy-17a-(methyloximino)-17a-homoestra-1,3,5(10)-trien-3-ylsulfamate 19) 2,17aβ-Dimethoxy-17a-homoestra-1,3,5(10)-trien-3-ylsulfamate 20) 2,17aβ-Dimethoxy-17a-homoestra-1,3,5(10)-trien-3-yl(N-acetyl)-sulfamate 21)17aβ-Ethoxy-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate 22)17aβ-Ethoxy-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl(N-acetyl)-sulfamate 23)2-Methoxy-17aβ-(n-propoxy)-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate24) 2-Methoxy-17aβ-methyl-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate25) 17aβ-Difluoromethyl-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-ylsulfamate 26)17aβ-Fluoromethyl-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate27) 17aβ-Ethyl-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate28) 2-Methoxy-17a(20)-methylene-17a-homoestra-1,3,5(10)-trien-3-ylsulfamate 29)17a(20)-Difluoromethylene-2-methoxy-17a-homoestra-1,3,5(110)-trien-3-ylsulfamate 30)17a(20)-Fluoromethylene-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-ylsulfamate 31) 2-Methoxy-17a-oxo-17a,18a-dihomoestra-1,3,5(10)-trien-3-ylsulfamate 32) 2-Methoxy-17a-oxo-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl(N-acetyl)-sulfamate 33)2-Methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate 34)2-Methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl (N-acetyl)-sulfamate35) 2-Methoxy-6-oximino-17a,18a-dihomoestra-1,3,5(10)-trien-3-ylsulfamate 36)2-Methoxy-6-(O-methyloximino)-17a,18a-dihomoestra-1,3,5(10)-trien-3-ylsulfamate 37)6α-Hydroxy-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate38) 6α-Acetylamino-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-ylsulfamate 39)17aβ-Hydroxy-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-ylsulfamate 40) 2-Methoxy-17a,18a-dihomoestra-1,3,5(10)-triene-3,17aβ-diylbissulfamate 41)2-Methoxy-17a,18a-dihomoestra-1,3,5(10)-triene-3,17aβ-diylbis-(N-acetyl)-sulfamate 42)17a-Difluoro-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-ylsulfamate 43)17aα-Fluoro-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate44) 17aβ-Fluoro-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-ylsulfamate 45)2-Methoxy-17a-oximino-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate46)2-Methoxy-17a-(methyloximino)-17a,18a-dihomoestra-1,3,5(10)-trien-3-ylsulfamate 47) 2,17aβ-Dimethoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-ylsulfamate 48)17aβ-Ethoxy-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate49) 2-Methoxy-17aβ-(n-propoxy)-17a,18a-dihomoestra-1,3,5(10)-trien-3-ylsulfamate 50)2-Methoxy-17aβ-methyl-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate51) 17aβ-Difluoromethyl-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate 52)17aβ-Fluoromethyl-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-ylsulfamate 53)17aβ-Ethyl-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate54) 2-Methoxy-17a(20)-methylene-17a,18a-dihomoestra-1,3,5(10)-trien-3-ylsulfamate 55)17a(20)-Difluoromethylene-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-ylsulfamate 56)17a(20)-Fluoromethylene-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-ylsulfamate 57) 2-Ethyl-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-ylsulfamate 58) 2-Ethyl-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-yl(N-acetyl)-sulfamate 59) 2-Ethyl-17a-homoestra-1,3,5(10)-trien-3-ylsulfamate 60) 2-Ethyl-17a-homoestra-1,3,5(10)-trien-3-yl(N-acetyl)-sulfamate 61)2-Ethyl-17aβ-hydroxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate 62)2-Ethyl-17a-homoestra-1,3,5(10)-triene-3,17aβ-diyl bissulfamate 63)2-Ethyl-17a-homoestra-1,3,5(10)-triene-3,17aβ-diylbis-(N-acetyl)-sulfamate 64)2-Ethyl-17aβ-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate or 65)2-Ethyl-17aβ-ethoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate.
 11. Apharmaceutical composition comprising at least one compound of formula Iaccording to claim 1 and a pharmaceutically compatible carrier andoptionally one or more additional active ingredients.
 12. A method ofpreparing a pharmaceutical composition according to claim 11, comprisingbringing together into a composition a 2-substitutedD-homoestra-1,3,5(10)-trien-3-yl sulfamate and a pharmaceuticallyacceptable carrier.
 13. A method for treating a tumor disease that canbe positively influenced by the inhibition of tubulin polymerization,wherein said tumor disease is selected from the group consisting ofbreast cancer, prostate cancer, colon cancer, non-small-cell-lung cancerand primary dermal microvascular endothelial cell proliferationcomprising administering to a subject in need thereof an effectiveamount of a 2-Substituted D-homoestra-1,3,5(10)-trien-3-yl sulfamateaccording to claim
 1. 14. A method according to claim 13, furthercomprising administering at least one additional active ingredient. 15.A method according to claim 13, wherein the disease treated is a diseaseof a male or female gonad, of a male or female sex organ, or of amammary gland, that can be positively influenced by the inhibition oftubulin polymerization and wherein said disease is selected from thegroup consisting of breast cancer, prostate cancer, colon cancer,non-small-cell-lung cancer and primary dermal microvascular endothelialcell proliferation.
 16. A method according to claim 13, which is fortreating breast cancer.
 17. A method according to claim 13, which is fortreating prostate cancer.
 18. A method according to claim 13, which isfor treating colon cancer, non-small-cell-lung cancer, or primary dermalmicrovascular endothelial cell proliferation.
 19. A method for treatingbreast cancer comprising administering to a subject in need thereof aneffective amount of a 2-Substituted D-homoestra-1,3,5(10)-trien-3-ylsulfamate according to claim
 1. 20. A method for treating prostatecancer comprising administering to a subject in need thereof aneffective amount of a 2-Substituted D-homoestra-1,3,5(10)-trien-3-ylsulfamate according to claim
 1. 21. A method for treating colon cancercomprising administering to a subject in need thereof an effectiveamount of a 2-Substituted D-homoestra-1,3,5(10)-trien-3-yl sulfamateaccording to claim
 1. 22. A method for treating non-small-cell-lungcancer comprising administering to a subject in need thereof aneffective amount of a 2-Substituted D-homoestra-1,3,5(10)-trien-3-ylsulfamate according to claim
 1. 23. A method for treating primary dermalmicrovascular endothelial cell proliferation comprising administering toa subject in need thereof an effective amount of a 2-SubstitutedD-homoestra-1,3,5(10)-trien-3-yl sulfamate according to claim
 1. 24. Amethod for treating breast cancer, prostate cancer, colon cancer,non-small-cell-lung cancer, or primary dermal microvascular endothelialcell proliferation comprising administering to a subject in need thereofan effective amount of a 2-Substituted D-homoestra-1,3,5(10)-trien-3-ylsulfamate according to claim 10.